This Application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsin S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. An increase in cathepsin S activity contributes to the pathology and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases.
This Application relates to compounds of Formula I: 
in which:
X1 and X2 are both methylene or X1 is ethylene and X2 is a bond;
R1 is hydrogen and R2 is cyano, hetero(C5)aryl or (C1-4)alkyl-substituted hetero(C5)aryl or both R1 and R2 are hydrogen, halo, (C1-4)alkyl or xe2x80x94X3OR9, wherein X3 and R9 are as defined below, or R1 and R2 together with the carbon atom to which both R1 and R2 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
R3 is xe2x80x94CR5xe2x95x90CHR6 or xe2x80x94CR7xe2x95x90NR8, wherein R5 and R6 together with the atoms to which R5 and R6 are attached form (C2-6)alkenyl, (C5-12)cycloalkenyl, hetero(C5-12)cycloalkenyl, (C6-12)aryl, hetero(C6-12)aryl, (C9-12)bicycloaryl or hetero(C8-12)bicycloaryl and R7 and R8 together with the atoms to which R7 and R8 are attached form hetero(C5-12)cycloalkenyl, hetero(C6-12)aryl or hetero(C8-12)bicycloaryl, wherein R3 optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; and
R4 is xe2x80x94C(O)X4R11 or xe2x80x94S(O)2X4R11, wherein X4 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR12xe2x80x94, wherein R12 is hydrogen or (C1-6)alkyl, and R11 is (i) (C1-6)alkyl optionally substituted by xe2x80x94OR3, xe2x80x94SR3, xe2x80x94S(O)R3, xe2x80x94S(O)2R13, xe2x80x94C(O)R13, xe2x80x94C(O)OR3, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, xe2x80x94NR14C(O)R13, xe2x80x94NR14C(O)OR13, xe2x80x94NR14C(O)NR13R14 or xe2x80x94NR14C(NR14)NR13R14, wherein R13 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl and R14 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkly, (C9-12)bicycloaryl(C0-3)alkyl or hetero(C8-12)bicycloaryl(C0-3)alkyl or (iii) (C3-6)cycloalkyl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl substituted by xe2x80x94X5OR15, xe2x80x94X5SR15, xe2x80x94X5S(O)R15, xe2x80x94X5S(O)2R15, xe2x80x94X5C(O)R 15, xe2x80x94X5C(O)OR15, xe2x80x94X5C(O)NR15R16, xe2x80x94X5NR15R16, xe2x80x94X5NR16C(O)R15, xe2x80x94X5NR16C(O)OR15, xe2x80x94X5NR16C(O)NR15R16 or xe2x80x94X5NR16C(NR16)NR15R16, wherein X5 is a bond or methylene, R15 is (C3-6)cycloalkyl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl, phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl and R16 is hydrogen or (C1-6)alkyl; wherein R4 optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, nitro, halo-substituted (C1-3)alkyl, xe2x80x94X5NR17R17, xe2x80x94X5NR17C(O)OR17, xe2x80x94X5NR17C(O)NR17R17, xe2x80x94X5NR17C(NR17)NR17R17, xe2x80x94X5OR17xe2x80x94X5SR17, xe2x80x94X5C(O)OR17, xe2x80x94X5C(O)NR17R17, xe2x80x94X5S(O)2NR17R17, xe2x80x94X5P(O)(OR8)OR17, xe2x80x94X5OP(O)(OR8)OR17, xe2x80x94X5NR17C(O)R18, xe2x80x94X5S(O)R18, xe2x80x94X5S(O)2R18 and xe2x80x94X5C(O)R18 and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, xe2x80x94NR17R17, xe2x80x94NR C(O)OR17, xe2x80x94NR17C(O)NR17R17, xe2x80x94NR17C(NR17)NR17R17, xe2x80x94OR17, xe2x80x94SR17, xe2x80x94C(O)OR17, xe2x80x94C(O)NR17R17, xe2x80x94S(O)2NR17R17, xe2x80x94P(O)(OR17)OR17, xe2x80x94OP(O)(OR17) OR17, xe2x80x94NR17C(O)R18, xe2x80x94S(O)R18, xe2x80x94S(O)2R18 and xe2x80x94C(O)R18, wherein X5 is a bond or (C1-6)alkylene, R17 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R18 is (C1-6)alkyl or halo-substituted (C1-3)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
A second aspect of the invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
A third aspect of the invention is a method for treating a disease in an animal in which inhibition of cathepsin S can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof.
A fourth aspect of the invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof.
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by a straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkylxe2x80x9d represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-12)aryl(C0-3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C1-6)alkylene includes methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94) 2-butenylene (xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94), 2-methyltetramethylene (xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94) and the like).
xe2x80x9cAlkenylxe2x80x9d means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond. Hence, optionally substituted (C2-6)alkenyl as used in this Application to define R3 includes 2-bromovinyl (xe2x80x94CHxe2x95x90CHBr), buta-1,3-dienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH2), 2-chloro-1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CClxe2x80x94CH3), 2-chlorovinyl (xe2x80x94CHxe2x95x90CHCl), 4-isopropenyl (xe2x80x94C(CH3)xe2x95x90CH2), 1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3), 2-methylpropenyl (xe2x80x94CHxe2x95x90C(CH3)2), 2-nitrovinyl (xe2x80x94CHxe2x95x90CHNO2), propenyl (xe2x80x94CHxe2x95x90CHxe2x80x94CH3), 2-trifluormethylvinyl (xe2x80x94CHxe2x95x90CHxe2x80x94CF3), trifluorovinyl (xe2x80x94CFxe2x95x90CF2), vinyl (xe2x80x94CHxe2x95x90CH2), and the like).
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylidene includes methylene (xe2x95x90CH2), ethylidene (xe2x95x90CHCH3), isopropylidene (xe2x95x90C(CH3)2), propylidene (xe2x95x90CHCH2CH3), allylidene (xe2x95x90CHCHxe2x95x90CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example, optionally substituted (C6-12)aryl as used in this Application to define R3 includes biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo-5-fluorophenyl, 4-tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 4-chlorocarbonylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl, 2-ethoxycarbonylphenyl, 2-fluoropheny, 2-lodophenyl, 4-isopropylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, and the like. Optionally substituted (C6-12)aryl as used in this Application to define R4 includes 3-acetylphenyl, 3-tert-butoxycarbonylaminomethylphenyl, biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, naphth-2-yl, 3-phenoxyphenyl, phenyl, and the like.
xe2x80x9cBicycloarylxe2x80x9d means a bicyclic ring assembly containing the number of ring carbon atoms indicated, wherein the rings are linked by a single bond or fused and one, but not both, of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C9-12)bicycloaryl includes cyclohexylphenyl, 1,2-dihydronaphthyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, phenylcyclohexyl, 1,2,3,4-tetrahydronaphthyl, and the like).
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarbocyclic ketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means cycloalkyl, as defined in this Application, provided that the ring assembly is comprised of at least one double bond. Hence, optionally substituted (C5-12)cycloalkenyl as used in this Application to define R3 includes cyclopent-1-enyl, 2-methylcyclopent-1-enyl, 2-nitrocyclopent-1-enyl, 2-fluorocyclopent-1-enyl, 2-chlorocyclopent-1-enyl, 2-trifluoromethylcyclopent-1-enyl, cyclohex-1-enyl, 2-methylcyclohex-1-enyl, 2-nitrocyclohex-1-enyl, 2-fluorocyclohex-1-enyl, 2-chlorocyclohex-1-enyl, 3-cyclohexa-1,3-dienyl, and the like).
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3-12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).
xe2x80x9cCycloalkylenexe2x80x9d means a divalent saturated or partially unsaturated, monocyclic ring or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, the instance wherein xe2x80x9cR1 and R2 together with the carbon atom to which both R1 and R2 are attached form (C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
xe2x80x9cHalo-substituted alkylxe2x80x9d, as an isolated group or part of a larger group, means xe2x80x9calkylxe2x80x9d substituted by one or more xe2x80x9chaloxe2x80x9d atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
xe2x80x9cHeteroatom moietyxe2x80x9d includes xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group.
xe2x80x9cHeterocycloalkylenexe2x80x9d means cycloalkylene, as defined in this Application, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94S(O)2xe2x80x94, wherein R is hydrogen or (C1-6)alkyl. For example, the instance wherein R1 and R2 together with the carbon atom to which both R1 and R2 are attached form hetero(C3-8)cycloalkylenexe2x80x9d includes, but is not limited to, the following: 
in which R is hydrogen, (C1-6)alkyl, or a protecting group.
xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and each ring is comprised of 5 or 6 ring atoms. For example, optionally substituted hetero(C5-12)aryl as used in this Application to define R3 includes 4-amino-2-hydroxypyrimidin-5-yl, benzothiazol-2-yl, 1H-benzoimidazol-2-yl, 2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl, 5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-4,6-dimethylpyrid-3-yl, 8-hydroxy-5,7-dimethylquinolin-2-yl, 5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl, 2-methylfur-3-yl, 5-methylfur-2-yl, 1-methyl-1H-imidazol-2-yl, 5-methyl-3H-imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-2H-pyrazol-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl, 2-methylthiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazol-4-yl, pyridazin-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H-[1,2,4]triazol-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1H-pyrrol-3-yl, quinolin-2-yl, 1H-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl, thien-2-yl, thien-3-yl, 2H-[1,2,4]triazol-3-yl, 3H-[1,2,3]triazol-4-yl, 5-trifluoromethylpyrid-2-yl, and the like Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. Optionally substituted hetero(C5-12)aryl as used in this Application to define R4 includes benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl, thien-2-yl, thien-3-yl, and the like.
xe2x80x9cHeterobicycloarylxe2x80x9d means bicycloaryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, optionally substituted hetero(C8-12)bicycloaryl as used in this Application to define R3 includes 2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In general, the term heterobicycloaryl as used in this Application includes, for example, benzo[1,3]dioxol-5-ylcarbonyl, 3,4-dihydro-2H-[1,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 1,2,3,4,5,6-hexahydro[2,2xe2x80x2]bipyridinylyl, morpholinylpyridyl, 3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, piperidinylphenyl, 5,6,7,8-tetrahydroquinolinyl, and the like. For example, hetero(C5-12)aryl as used in this Application to define R4 includes benzo[1,3]dioxol-5-yl. For example, hetero(C8-12)bicycloaryl(C0-3)alkyl used to describe R11 in this Application, includes 1-oxo-1,3-dihydroisoindol-2-yl, quinolin-3-yl, quinolin-2-yl, 3a,7a-dihydrobenzo[1,3]-dioxol-5-yl, naphthalen-2-yl, 3-chlorobenzo[b]thiophen-2-yl, benzo[b]thiophen-2-yl and 1H-indol-5-yl, and the like.
xe2x80x9cHeterocycloalkenylxe2x80x9d means heterocycloalkyl, as defined in this Application, provided that the ring assembly is comprised of at least one double bond. Hence, optionally substituted hetero(C5-12)cycloalkenyl as used in this Application to define R3 includes 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl, 2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl, 5-hydroxy-4-oxo-4H-pyran-2-yl, 5-methoxy-4-oxo-4H-pyran-2-yl, 6-oxo-1,6-dihydropyrimidin-5-yl, 4-oxo-1,4-dihydropyrid-2-yl, 6-oxo-1,6-dihydropyrid-2-yl, 6-oxo-1,6-dihydropyrid-3-yl, and the like).
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term hetero(C5-12)cycloalkyl includes [1,4xe2x80x2]bipiperidinylyl, 1xe2x80x2,2xe2x80x2-dihydro-2H-[1,4xe2x80x2]bipyridinylyl, imidazolidinyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). Thus, for example, optionally substituted hetero(C5-12)cycloalkyl as used in this Application to define R4 includes 4-tert-butoxycarbonylpiperazin-1-yl, 4-ethoxycarbonylpiperazin-1-yl, 4-fur-2-ylcarbonylpiperazin-1-yl, morpholin-4-yl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R4 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g., wherein R4 is 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHydroxyxe2x80x9d means the radical xe2x80x94OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.
xe2x80x9ciminoketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(NR)xe2x80x94, wherein R is hydrogen or (C1-6)alkyl.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomers or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition, March, Jerry, John Wiley and Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers. Thus , for example, the name N-[1-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide is meant to include N-[1S-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide and N-[1R-cyanomethylcarbamoyl-2-(4-methylbenzylsulfonyl)ethyl]benzamide and any mixture, racemic or otherwise, thereof.
xe2x80x9cKetone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cMethylenexe2x80x9d means the divalent radical xe2x80x94CH2xe2x80x94.
xe2x80x9cNitroxe2x80x9d means the radical xe2x80x94NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9cR3 optionally is substituted by 1 to 5 radicalsxe2x80x9d means that R3 may or may not be substituted in order to fall within the scope of the invention.
xe2x80x9cOrthoxe2x80x9d and xe2x80x9cmetaxe2x80x9d have the meaning typically associated with their usage in organic chemistry. Hence, the phrase xe2x80x9cR22 at the first occurrence is attached at the ring carbon ortho or meta to the 1-position of the phenyl moietyxe2x80x9d, refers to the following illustrative example: 
wherein R22 is attached at the 2 or 3-position.
xe2x80x9cN-oxide derivativesxe2x80x9d means derivatives of compounds of Formula I in which nitrogens are in an oxidized state (i.e., Oxe2x80x94N) and which possess the desired pharmacological activity.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. For example an ester of a compound of Formula I containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula I containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula I containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula I containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of compounds of Formula I containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cathepsin S inhibitors. A comprehensive list of suitable protecting groups can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cThioketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(S)xe2x80x94.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I in which R1 and R2 are each hydrogen, R3 is phenyl, X2 is methylene and R4 is naphthalen-2-yl-methanoyl; that is, a compound having the following structure: 
is named N-(2-benzylsulfonyl-1R-cyanomethylcarbamoylethyl)naphthalene-2-carboxamide or naphthalene-2-carboxylic acid [(R)-1-(cyanomethyl-carbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;
While the broadest definition of the invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. For example, R1 particularly represents hydrogen and R2 represent hydrogen, hetero(C5)aryl or (C1-4)alkyl-substituted hetero(C5)aryl or together with the carbon atom to which both R1 and R2 are attached form (C3-5)cycloalkylene or (C5-6)heterocycloalkylene.
Preferably X1 and X2 are both methylene and R3 represents (C2-6)alkenyl, (C6-12)aryl or hetero(C5-12)aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R3 more preferably represents biphenyl, isooxazolyl, naphthyl, phenyl, pyridyl, thienyl or vinyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl. R3 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 4-tert-butylphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dimethylisooxaxol-4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, prop-2-en-1-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulfanylphenyl, 3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-trifluorophenyl or 2,3,6-trifluorophenyl.
In particular, X1, X2 and R3 along with the sulfonyl moiety to which X1 and X2 are attached together represent a group having the following formula: 
in which n is 0, 1, 2, 4 or 5 and R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X3NR9R9, xe2x80x94X3OR9, xe2x80x94X3SR9, xe2x80x94X3C(O)NR9R9, xe2x80x94X3C(O)OR9, xe2x80x94X3S(O)R10, xe2x80x94X3S(O)2R10 and xe2x80x94X3C(O)R10, wherein X3 is a bond or (C1-2)alkylene, R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R10 is (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which n is 0, 1 or 2 and R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94OR9, xe2x80x94SR9 and xe2x80x94C(O)OR9, wherein R9 at each occurrence independently is hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl; more particularly in which R22 at each occurrence independently is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl; more particularly in which at the first occurrence is attached at the ring carbon ortho or meta to the 1-position of the phenyl moiety.
Preferably n is 1 or 2 and R22 at the first occurrence is selected from a group consisting of difluoromethoxy, trifluoromethoxy, trifluorosulfanyl and nitro and R22 at the second occurrence, if present, is selected from a group consisting of (C1-4)alkyl, bromo, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfanyl. Preferably R22 at the first occurrence is in the ortho position.
R4 preferably may represent xe2x80x94C(O)X4R11 or xe2x80x94S(O)2X4R11, wherein X4 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR12xe2x80x94, wherein R12 is hydrogen or (C1-6)alkyl, and R11 is (C1-6)alkyl, (C3-12)cycloalkyl(C0-3)alkyl, hetero(C5-12)cycloalkyl(C0-3)alkyl, (C6-10)aryl(C0-3)alkyl, hetero(C5-10)aryl(C0-3)alkyl, hetero(C8-12)bicycloaryl(C0-3)alkyl, hetero(C5-6)cycloalkyl(C0-3)alkyl or phenyl(C0-3)alkyl, wherein the hetero(C5-6)cycloalkyl or phenyl is substituted in the ring by xe2x80x94X5OR15 or xe2x80x94X5C(O)R15, wherein X5 is a bond or methylene and R15 is phenyl(C0-3)alkyl or hetero(C5-6)aryl(C0-3)alkyl, wherein any aryl or heteroaryl group comprising R4 optionally is substituted in the ring by 1 to 2 substituents selected from (C1-6)alkyl, halo, halo-substituted (C1-3)alkyl, xe2x80x94X5OR17, xe2x80x94X5NR17C(O)OR17, xe2x80x94X5C(O)OR17 or xe2x80x94X5C(O)R18, wherein X5 is a bond or (C1-6)alkylene, R17 is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R18 is (C1-6)alkyl or halo-substituted (C1-3)alkyl. R4 more preferably may represent 3-acetylbenzoyl, allyloxycarbonyl, 2-aminopyrid-3-ylcarbonyl, 6-aminopyrid-3-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, benzoyl, 4-benzoylbenzoylcarbonyl, benzo[1,3]dioxol-3-ylcarbonyl, benzofur-2-ylcarbonyl, biphenyl-4-ylcarbonyl, 4-bromobenzoyl, 3-bromothien-2-yl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminomethylbenzoyl, 4-teir-butoxycarbonylpiperazin-1-ylcarbonyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 3-chlorothienylcarbonyl, cyclopentylcarbonyl, 3,4-difluorobenzoyl, 3,4-dimethoxybenzoyl, dimethylcarbamoyl, 4-ethoxycarbonylpiperazin-1-ylcarbonyl, 4-fluorobenzoyl, 3-fluoro-4-methoxybenzoyl, fur-2-ylcarbonyl, fur-3-ylcarbonyl, 4-fur-2-ylcarbonylpiperazin-1-ylcarbonyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 4-hydroxypyrid-3-yl, 6-hydroxypyrid-3-yl, 1H-indol-4-ylcarbonyl, isopropylcarbamoyl, isobutyloxycarbonyl, isopropyloxycarbonyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 3-methylbenzoyl, 5-methylthienylcarbonyl, 4-methylvaleryl, morpholin-4-ylcarbonyl, naphth-2-ylcarbonyl, naphth-2-ylsulfonyl, 3-phenoxybenzoyl, 3-phenylacryloyl, phenylsulfonyl, pyrazin-2-ylcarbonyl, 3-pyrid-3-ylacryl, pyrid-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, quinol-2-ylcarbonyl, quinol-3-ylcarbonyl, thien-2-ylcarbonyl, thien-3-ylcarbonyl, thien-2-ylsulfonyl, 4-trifluoromethoxybenzoyl or 4-trifluoromethylbenzoyl.
R4 more preferably is benzoyl, morpholin-4-ylcarbonyl, thienylcarbonyl, indolylcarbonyl or pyridinylcarbonyl, optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl. In particular, R4 represents one of the following formulae: 
namely benzoyl, morpholin-4-ylcarbonyl, thien-2-yl, thien-3-yl, indol-4-yl and pyridin-4-yl, respectively, optionally substituted in the ring by 1 to 2 substituents selected from fluoro and methyl.
Preferred are compounds of Formula II: 
in which n is 1, 2, 3, 4 or 5 and each R1, R2, R3 and R22 are as defined in the Summary of the Invention and in the preferred embodiments.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups.
Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (A1 to A36 or A40 to A71) shown in Table 1 to the nitrogen atom (N*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2, and joining the methine carbon atom (CH*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2 to the acyl carbon atom (C*) of one of the acyl-aminoalkylnitrile fragments(C1 to C9) depicted in Table 3.
Further particular compounds of the invention are selected from the compounds formed by joining the sulphonyl atom (SO2*) of one of the fragments (A37 to A39) shown in Table 1 to the nitrogen atom (N*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2, and joining the methine carbon atom (CH*) of one of the substituted aminoalkyl fragments (B1 to B75) shown in Table 2 to the acyl carbon atom (C*) of one of the acyl-aminoalkylnitrile fragments(C1 to C9) depicted in Table 3.
Thus, for example, in the above list the compound denoted as A20-B2-C1 is the product of the combination of group A20 in Table 1 and B2 in Table 2 and C1 in Table 3, namely N-(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-hydroxy-benzamide: 
Further preferred are compounds of Formula I selected from a group consisting of:
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A24-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A25-B2-C1);
Pytidine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A62-B2-C1);
Pyrazine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A63-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A65-B2-C1);
2-Amino-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A67-B 2xe2x80x94C1);
6-Amino-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-nicotinamide, (compound denoted as A66-B2-C1);
3-Hydroxy-pyridine-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A68-B2-C1);
Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-[2-1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A2-B2-C4);
Morpholine-4-carboxylic acid-{(R)-1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide (compound denoted as A2-B2-C5);
(R)-N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(3,3-dimethyl-ureido)-propionamide, (compound denoted as A56-B2-C1);
{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-carbamic acid allyl ester, (compound denoted as A53-B2-C1);
{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-carbamic acid isobutyl ester, (compound denoted as A51-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-3,4-difluro-benzamide, (compound denoted as A46-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A48-B2-C1);
Thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A28-B2-C1);
4-Bromo-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A43-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A44-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-4-trifluoromethoxy-benzamide, (compound denoted as A45-B2-C1);
Naphthalene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A7-B2-C1);
(E)-N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-phenyl-acrylamide, (compound denoted as A59-B2-C1);
5-Methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A31-B2-C1);
Biphenyl-4-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A11-B2-C1);
1H-Indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A60-B2-C1);
Benzo[1,3]dioxole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A8-B2-C1);
Benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-amide, (compound denoted as A35-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A69-B2-C1);
Quinoline-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A 13-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A70-B2-C1);
4-Chloro-N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A42-B2-C1);
N-{(R)-1-(Cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A41-B2-C1);
3-Bromo-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A33-B2-C1);
3-Chloro-benzo[b]thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A36-B2-C1);
3-Chloro-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A32-B2-C1);
N-{(R)-(Cyanomethyl-carbamoyl)-[2-(1,1-difluoro-methoxy)-phenylmethane-sulfonyl]-ethyl}-benzamide, (compound denoted as A40-B2-C1);
(R)-N-Cyanomethyl-3-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-2-(naphthalene-2-sulfonylamino)-propionamide, (compound denoted as A38-B2-C1);
Cyclopentanecarboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A34-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(3-trifluromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B2-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-trifluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B42-C1);
N-(1R-cyanomethylcarbamoyl-2-(3-difluoromethoxybenzylsulfonyl)ethyl]benzamide, (compound denoted as A1-B24-C1);
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C1);
N-[1R-(i-cyanocyclopropylcarbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)ethyl]-morpholine-4-carboxamide, (compound denoted as A2-B2-C3); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
Particularly preferred are compounds of Formula I selected from a group consisting of:
N-[1R-cyanomethylcarbamoyl-2-(2-difluoromethoxybenzylsulfonyl)ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C1);
thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A28-B2-C1);
thiophene-3-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A29-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-benzamide, (compound denoted as A49-B2-C1);
morpholine-4-carboxylic acid-{(R)-1-(4-cyano-1-methyl-piperidin-4-ylcabamoyl)-2-[2(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A2-B2-C5);
5-methyl-thiophene-2-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A31-B2-C1);
1H-indole-5-carboxylic acid-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-(1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-amide, (compound denoted as A60-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A2-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-3-methyl-benzamide, (compound denoted as A46-B2-C1);
N-{(R)-1-(cyanomethyl-carbamoyl)-2-[2-( 1,1-difluoro-methoxy)-phenylmethanesulfonyl]-ethyl}-isonicotinamide, (compound denoted as A25-B2-C1);
N-[1R-(1-cyanocyclopropyl-carbamoyl)-2-(2-difluoromethoxybenzylsulfonyl)-ethyl]morpholine-4-carboxamide, (compound denoted as A2-B2-C3); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
The compounds of the invention are selective inhibitors of cathepsin S and, as such, are useful for treating diseases in which cathepsin S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts.
Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 11,12, 13 and 14, infra.
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from about 1 micrograms per kilogram body weight (xcexcg/kg) per day to about 1 milligram per kilogram body weight (mg/kg) per day, typically from about 10 xcexcg/kg/day to about 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from about 100 xcexcg/day to about 100 mg/day, typically from about 1 xcexcg/day to about 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01%w to 10%w, preferably 0.3%w to 1%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 15.
Processes for Making Compounds of Formula I:
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 1: 
in which each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing an acid of Formula 2 with an aminoalkanonitrile of the formula NH2CR1R2CN and then oxidizing. The condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium hex afluorophosphate (PyBOP(copyright)), 1-(3-dimethylaminopropyl)-3-ehtylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotrizol-1-yl)-1,1,3,3, tetra-methyluroniumhexafluorophosphate (HATU), or the like) and non-nucleophilic base (e.g., N-methylpyrrolidinone, N-methylmorpholine, and the like, or any suitable combination thereof) at ambient temperature and requires 5 to 10 hours to complete.
The oxidation can be carried out with an oxidizing agent (e.g., Oxone(copyright), or the like) in a suitable solvent (e.g., methanol, water, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete. A detailed description for the synthesis of a compound of Formula I by the processes in Reaction Scheme 1 is set forth in the Examples 1, 2, 8 and 10, infra.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 2: 
in which n is 0 or 2, L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing a compound of Formula 3 with a compound of the formula R4L (e.g., 3-acetylbenzoic acid, nicotinic acid, morpholin-4-ylcarbonyl chloride, or the like) and then oxidizing when n is 0. When L is chloro the condensation can be carried out at ambient temperature in the presence of a suitable non-nucleophilic base (e.g., triethylamine, N-methylmorpholine, or the like) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, or the like) and requires 16 to 24 hours to complete. When L is hydroxy the condensation typically is effected in the presence of a suitable coupling agent (e.g., (PyBOP(copyright)), EDCI, HBTU, DCC, or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or the like) in a suitable solvent (e.g., dichloromethane, tetrahydrofuran, or the like, or any suitable combination thereof) at ambient temperature and requires 16 to 24 hours to complete.
The oxidization can be carried out by the process described above for Reaction Scheme 1. Detailed procedures for the syntheses of compounds of Formula I by the processes described in Scheme 2 are set forth in the Examples 3, 4 and 5, infra.
Compounds of Formula I in which R4 is xe2x80x94NR13R14 or xe2x80x94NR20R21 can be prepared by proceeding as in the following Reaction Scheme 3: 
in which R19 is xe2x80x94NR13R14 or NR20R21, wherein R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and each X1, X2, R1, R2, R3, R13 and R14 are as defined in the Summary of the Invention.
Compounds of Formula I in which R4 is xe2x80x94C(O)NR13R14 or xe2x80x94C(O)NR20R21, wherein R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and R13 and R14 are as defined in the Summary of the Invention can be prepared by condensing a compound of Formula 4 with a compound of the formula NHR13R14 or NHR20R21, respectively, and then oxidizing when n is 0. The condensation reaction can be carried out at ambient temperature in a suitable solvent (e.g., dichloromethane, or the like) and requires 16 to 24 hours to complete. The oxidization can be carried out by the process described above for Reaction Scheme 1. A detailed description for the synthesis of a compound of Formula I by the processes in Scheme 3 is set forth in the Example 6, infra.
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 4: 
in which L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined for Formula I in the Summary of the Invention.
Compounds of Formula I can be prepared by reacting a compound of Formula 5 with a compound of the formula R3X2L and then oxidizing. The reaction is carried out in the presence of base (e.g., potassium hydroxide, or the like) at ambient temperature and requires 2 to 3 hours to complete. The oxidization can be carried out by the process described above for Reaction Scheme 1. A detailed description for the synthesis of a compound of Formula I by the processes in Scheme 4 is set forth in the Examples 7 and 9, infra.
Compounds of Formula 2 can be prepared by reacting a compound of Formula 6: 
with a compound of the formula R4L, in which L is a leaving group and X1, X2 and R3 are as defined in the Summary of the Invention. The reaction can be carried out in the presence of base (e.g., 1 N aqueous sodium hydroxide, or the like) at about 0.5xc2x0 C. A detailed description for the synthesis of a compound of Formula 2 by the processes described above is set forth in the References 1 and 7, infra. Compounds of Formula 6 are commercially available or otherwise can be prepared by methods known in the art or analogous to those described elsewhere in this Application.
Compounds of Formula 2 in which X1 is ethylene can be prepared by condensing a diester of Formula 7: 
with a compound of the formula R3SCH2CH2L to provide a compound of Formula 8: 
in which L is a leaving group and R3 and R4 are as defined in the Summary of the Invention, decarbalkoxylating to provide a corresponding monoester and then converting the monoester to a corresponding carboxylic acid. The condensation reaction can be carried out in the presence of a suitable nonnucleophilic base (e.g., N-methylpyrrolidone) and lithium hydroxide. The decarbalkoxylation can be effected under strongly basic conditions (e.g., in the presence of 1 N aqueous sodium hydroxide) in a suitable solvent (e.g, methanol) and requires 4 to 6 hours to complete. A detailed description for the synthesis of a compound of Formula 2 by the processes described above is set forth in the Reference 2, infra.
Compounds of Formula 3 can be prepared by condensing a compound of Formula 9: 
with an aminoalkanonitrile of the formula NH2CR1R2CN, in which PG is a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention, group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention, with an appropriate condensing agent (e.g., N,N-dicyclohexyldiimide, diisopropylcarbodiimide, carbonyldiimidazole, or the like) and a suitable non-nucleophilic base (e.g., N-methylpyrrolidinone, N-methylmorpholine, or the like, or any suitable combination thereof) in a suitable solvent (e.g., dichloromethane, or the like) at ambient temperature and requires 2 to 3 days to complete. Oxidization can be carried out by the process described above for Reaction Scheme 1. Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999. A convenient method of deprotecting is by treatment with a suitable acid (e.g., p-toluenesulfonic acid, or the like) providing the acid addition salt in the process. A detailed description for the synthesis of a compound of Formula 3 by the processes described above is set forth in the References 3, 4 and 5, infra. Compounds of Formula 4 can be prepared by reacting a compound of Formula 3 with phosgene. The reaction is carried out conveniently in a biphasic solvent (e.g., an equal mixture of dichloromethane and saturated sodium bicarbonate solution at ambient temperature. A detailed description for the synthesis of a compound of Formula 4 by the processes described above is set forth in the Reference 6, infra.
Compounds of Formula 5 can be prepared by sequentially condensing an acid of Formula 10: 
with an aminoalkanonitrile of the formula NHR2CR3R4CN and a compound of the formula R4L and then deprotecting. The condensation reaction is carried out in a fashion analogous to the process described above for the preparation of the compounds of Formula 3. The condensation reaction with the compound of the formula R4L is carried out in a fashion analogous to the process described above for the preparation of the compounds of Formula I by Scheme 2. The deprotection can be effected by treatment with a suitable reducing agent (e.g., tris-butyl phosphine, tris-carboxyethyl phosphine, or the like) in the presence of base (e.g., aqueous potassium hydroxide, or the like) in a suitable solvent (e.g., DMIF, or the like) under an inert atmosphere and at ambient temperature and requires 12 to 24 hours. A detailed description for the synthesis of a compound of Formula 5 by the processes decribed above is set forth in the Reference 8, infra.
Additional Processes for Preparing Compounds of Formula I:
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. 1999.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981).
In summary, the compounds of Formula I are made by a process which comprises:
(A) reacting a compound of Formula 2: 
with a compound of the formula NH2CR1R2CN, in which X1, X2, R1, R2, R3 and R4 are as defined in the Summary of the Invention for Formula I; or
(B) reacting a compound of Formula 3: 
with a compound of the formula R4L, in which n is 0 or 2, L is a leaving group and each X1, X2, R1, R2, R3 and R 4 are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or
(C) reacting a compound of Formula 4: 
with a compound of formula NHR13R14 or NHR20R21 to provide a compound of Formula I in which R4 is xe2x80x94C(O)NR13R14 or xe2x80x94C(O)NR2OR21, respectively, wherein n is 0 or 2, R20 and R21 together with the nitrogen atom to which R20 and R21 are attached form hetero(C5-12)cycloalkyl and each X1, X2, R1, R2, R3, R13 and R14 are as defined in the Summary of the Invention for Formula I, and then oxidizing when n is 0; or
(D) reacting a compound of Formula 5: 
with a compound of R3X2L in which L is a leaving group and each X1, X2, R1, R2, R3 and R4 are as defined in the Summary of the Invention for Formula I; and
(E) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(F) optionally converting a salt form of a compound of Formula I to non-salt form;
(G) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(H) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(I) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;
(J) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(K) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.